The invention relates to reducing hair growth in mammals, particularly for cosmetic purposes.
A main function of mammalian hair is to provide environmental protection. However, that function has largely been lost in humans, in whom hair is kept or removed from various parts of the body essentially for cosmetic reasons. For example, it is generally preferred to have hair on the scalp but not on the face.
Various procedures have been employed to remove unwanted hair, including shaving, electrolysis, depilatory creams or lotions, waxing, plucking, and therapeutic antiandrogens. These conventional procedures generally have drawbacks associated with them. Shaving, for instance, can cause nicks and cuts, and can leave a perception of an increase in the rate of hair regrowth. Shaving also can leave an undesirable stubble. Electrolysis, on the other hand, can keep a treated area free of hair for prolonged periods of time, but can be expensive, painful, and sometimes leaves scarring. Depilatory creams, though very effective, typically are not recommended for frequent use due to their high irritancy potential. Waxing and plucking can cause pain, discomfort, and poor removal of short hair. Finally, antiandrogens—which have been used to treat female hirsutism—can have unwanted side effects.
It has previously been disclosed that the rate and character of hair growth can be altered by applying to the skin inhibitors of certain enzymes. These inhibitors include inhibitors of 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase. See, for example, Breuer et al., U.S. Pat. No. 4,885,289; Shander, U.S. Pat. No. 4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007; Ahluwalia et al., U.S. Pat. No. 5,096,911; and Shander et al., U.S. Pat. No. 5,132,293.
The transient receptor potential (TRP) family of ion channels comprises more than 30 cation channels, and can be divided into seven main subfamilies: TRPC, TRPV, TRPM, TRPP, TRPML, TRPA, and the TRPN. Two members of two distinct subfamilies of TRP channels have been identified as being responsible for cold sensation: TRPM8 and TRPA1.
Transient Receptor Potential Melastatin-8 (TRPM8) belongs to the melastatin subfamily of TRP ion channels (Tominaga M. et al. (2004) J. Neurobiol. 61(1):3-12). TRPM8 is a Ca(2+)-permeable nonselective cation channel that mediates a direct influx of Ca(2+) ions in response to specific stimuli. It is activated by cold (temperatures below 24° C.) and by cooling compounds, such as menthol and icilin (Tsavaler et al. (2001) Cancer Res. 61(9):3760-9; McKemy et al. (2002) Nature 416:52-8; Peier et al. (2002) Cell 108(5):705-15). The TRPM8 channel is expressed in a subset of temperature-sensing small dorsal root and trigeminal ganglion neurons (McKemy et al. (2002) supra; Peier et al. (2002) supra; Babes et al. (2004) Eur J. Neurosci. 20(9):2276-82; Nealen et al. (2003) J. Neurophysiol. 90(1):515-20). The trigeminal ganglion neurons supply sensory nerves for facial skin areas above the mouth, the area of the lower jaw, as well as above the forehead and around the eye. Therefore, TRPM8 has been implicated in sensing cold temperatures at mammalian thermoreceptor nerve endings. In addition to its presence on sensory neurons, functional TRPM8 receptor has also been identified on various non-neuronal cell types. TRPM8 mRNA expression was reported at moderate levels in normal prostate tissue and appears to be elevated in prostate cancer, where it involves in a number of Ca(2+)-dependent processes, including proliferation and apoptosis (Thebault et al, 2005) J Biol Chem 280(47):39423-35). It is also expressed in a number of primary tumors of breast, colon, lung, and skin origin (Tsavaler et al. (2001) supra).
Another ion channel, transient receptor potential channel ankyrin-repeat 1 (TRPA1) also referred to as ankyrin-like protein 1 (ANKTM1) receptor is activated by cold temperatures (below 18° C.), cinnamaldehyde, allicin, eugenol, gingerol, and methyl salicylate, and similar to TRPM8, by icilin. TRPA1 is expressed in a subset of sensory neurons expressing nociceptive markers, such as TRPV1, calcitonin gene related peptide (CGRP) and substance P (Story et al. (2003) Cell 112:819-829). It has also been reported to be expressed in cultured fibroblasts, where it is down-regulated after fibroblast oncogenic transformation (Jaquemar et al. (1999) J. Biol. Chem. 274:7325-7333).